The epidemic of designer drug abuse has continued to be an extremely serious problem in the U.S. and elsewhere during the reporting period. These so-called bath salts designer drugs of abuse (e.g. MDPV and alpha-PVP) are powerful and extremely dangerous psychomotor stimulants that represent an ever-increasing and evolving threat to public health worldwide. Many such preparations have been seized by the authorities and most often contain synthetic derivatives of cathinone. MDPV, mephedrone, and methylone are among the most commonly identified bath salts in recent US seizures. Some of these drugs produce very bizarre, unpredictable, and irrational human behavioral effects. There are major problems in preventing the abuse of these drugs. First, these compounds are relatively simple and cheap to produce from chemicals readily available worldwide. Second, once the U.S. Drug Enforcement Administration (DEA) uses its emergency scheduling authority to place one generation of cathinones (MDPV, mephedrone, and methylone) under Schedule I (the most stringent) regulations, the next generation of structurally and pharmacologically-similar cathinone derivatives (e.g., MDPBP, MDPPP, alpha-PVP, and alpha-PPP) quickly emerge on the market as unregulated replacements. In addition, a large proportion of these substances are produced by Asian criminal groups that complicate interdiction efforts of the DEA and other law enforcement groups. This is not only a U.S. problem as nearly identical situations exist in Europe and elsewhere. As these new drugs appear it is necessary to rapidly assess the danger they present. Such studies in animals require substantial quantities of the pure, authentic drug substance in order to enable the appropriate studies in a timely manner. In order to gain further insight into the cathinones as a drug class, we synthesized and studied the pharmacologic properties and abuse potential of an array of cathinones including first- (MDPV) and select second-generation (MDPBP, MDPPP, alpha-PVP, and alpha-PPP) synthetic cathinones, and aimed to identify any structural determinants of their actions at monoamine transporters as well as their reinforcing potency and/or effectiveness. Both MDPV and alpha-PVP are chiral molecules. In order to determine the relative contribution of each enantiomer to the profile of the racemate, we separated the enantiomers of each by fractional crystallization of the salts with 2-bromotartranilic acid. This gave the MDPV enantiomers and the alpha-PVP enantiomers of at least 98% optical purity. We also determined the absolute configuration of these enantiomers by single crystal X-ray diffraction. Rats were trained to self-administer and rapidly acquired responding for each of the synthetic cathinones. The rank order of potency within each drug was S enantiomer>racemate R enantiomer.The reinforcing effects were highly correlated with their potency to inhibit uptake at DAT and NET, but not SERT. Our studies show that that both enantiomers of MDPV and alpha-PVP are highly effective reinforcers and play a role in the reinforcing effects of the racemates.